The present invention relates to an improved process for preparing 2-alkyl-3-aryl- and -heteroaryloxaziridines by oxidation of the corresponding aryl- or heteroarylaldimines using a peroxy compound.
2-tert-Butyl-3-phenyloxaziridine, for example, serves as starting material for preparing N-(tert-butyl)hydroxylamine, which is used for the synthesis of pharmaceutically active compounds.
It is already known (J. Am. Chem. Soc., 79, 5749 (1957)), that arylaldimines containing an unsubstituted or a nitro-substituted phenyl group can be covered with anhydrous peracetic acid into the corresponding oxaziridine which can be isolated by distillation and then hydrolyzed using aqueous-methanolic sulfuric acid, giving, after addition of alkali, the corresponding free N-alkylated hydroxylamine. The anhydrous peracetic acid required is prepared in situ from 90% strength aqueous hydrogen peroxide using excess acetic anhydride and catalytic amounts of sulfuric acid, in the solvent methylene chloride. The handling of such concentrated hydrogen peroxide solutions is associated with extremely high safety expenditure. Thus, if in any way possible, the preparation and handling of large amounts of such hydrogen peroxide solutions are avoided.
EP-B 217,269 discloses that N-alkyl-substituted aryloxaziridines are obtainable by reacting arylaldimines with perpropionic acid in benzene. To prevent hydrolysis of the arylaldimines and the aryloxaziridines under the acidic reaction conditions, the water content of the perpropionic acid has to be less than 0.1% by weight (“anhydrous perpropionic acid”). The preparation and handling of anhydrous perpropionic acid, too, is a process which requires high safety expenditure, in particular during the azeotropic distillation to remove the water.
Commercial m-chloroperbenzoic acid is a solid and, accordingly, easier to handle than peracetic acid or perpropionic acid. m-Chloroperbenzoic acid, too, has been used for oxidizing arylaldimines (J. Chem. Soc. Perkin Trans. 1 1990, 301 and 2390), the reaction being carried out in methylene chloride or methanol, i.e. a non-aqueous medium.
It is also known that benzylideneamino acid esters can be oxidized to the corresponding oxaziridines using monoperphthalic acids in the solvent diethyl ether (Tetrahedron Lett., 28, 2453 (1994)).
In general, the preparation and handling of percarboxylic acids is safer if water is present during their preparation and use, for example during oxidations. However, in the presence of acids and water, imines generally tend to hydrolyze. This is the reason why the presence of water has been substantially excluded in the known imine oxidations.
Furthermore, the presence of acid and water in the reaction medium used for preparing oxaziridines promotes hydrolytic cleavage of the oxaziridines formed into the corresponding aldehyde and the corresponding N-substituted hydroxylamine. The latter for its part is readily oxidized by the percarboxylic acid present to give the corresponding nitroso compound. Nitroso compounds are known to be substances which are highly carcinogenic. Accordingly, they have to be excluded in the preparation of intermediates for pharmaceutically active compounds.
According to WO 00/02848, the problem of the hydrolysis and the formation of undesirable subsequent products is solved by carrying out the oxidation with m-chloroperbenzoic acid in a two-phase system of toluene and an aqueous sodium carbonate solution. However, such a procedure is not recommended for realizing an industrial process, since two-phase reaction systems lead to upscaling problems which, if at all, can only be solved with great efforts.
None of the known methods for preparing aryloxaziridines by oxidizing arylamines with percarboxylic acids are satisfactory for industrial-scale processes. Accordingly, there is still a need for a simple, economical and low-risk process for preparing 2-alkyl-3-aryl- and heteroaryloxaziridines.